Pheromones act as both short-term olfactory cues that signal danger or the presence of mates, as well as long-term cues, which mediate changes in development and physiology via modulation of the neuroendocrine axis. Little is known about the mechanisms by which pheromone signals are transduced to modulate neurohormonal signaling in mammals, although dysregulation of this signaling can result in developmental and behavioral disorders. Olfactory signal transduction mechanisms are highly conserved across organisms, as are mechanisms of neuronal transmission, indicating that studying these processes in model organisms may provide insights into related processes in higher organisms. In C. elegans, the dauer pheromone regulates entry into the alternate dauer developmental stage via regulation of hormonal signaling, and provides an excellent model system in which to explore how pheromone signals are recognized and transduced to govern a critical developmental decision. The recent identification of both the structurally related ascarosides comprising dauer pheromone in C. elegans, and the first two pheromone receptors in C. elegans, whose mutants are defective in pheromone-mediated regulation of hormonal signaling, remains elusive in other model organisms. The goal of this proposal is to identify additional receptors required for pheromone signal transduction, and to characterize a gene required for inter-neuronal pheromone signal transmission. This work will contribute to our understanding of the pathways by which pheromones regulate critical behavioral and developmental decisions, and how dysfunction of these pathways can lead to impaired development, behavioral disorders, and obesity. The proposed specific aims are: 1. Identification of the neurons and receptors required for C3 ascaroside signal transduction ascaroside. 2. Identification of intercellular pheromone signaling pathways. PUBLIC HEALTH RELEVANCE: Pheromones are secreted molecules that communicate immediate and long-term signals among animals of the same species. For a complete understanding of how humans smell, and how odors affect development and behavior, a thorough understanding of the mechanisms of detecting and relaying pheromonal signals is necessary. This work will lead to a better understanding of how the brain processes chemical signals, and how dysfunction of the chemosensory system leads to impaired development, behavioral disorders, and obesity.